This invention relates to the preparation of ketorolac and its pharmaceutically acceptable salts, especially the tromethamine salt.
U.S. Pat. No. 4,089,969 (to Syntex (U.S.A.) Inc.) discloses various 5-(optionally substituted benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids, including ketorolac, (.+-.)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, of formula I, ##STR2##
the tromethamine salt of which is the active ingredient of the anti-inflammatory and analgesic drugs TORADOL.RTM. and ACULAR.RTM..
Various methods for the preparation of ketorolac and related pyrrolizine-1-carboxylic acids are exemplified in the patent and chemical literature, and many proceed through a common intermediate, 2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, or its alkyl esters. The alkyl esters may be readily 5-aroylated by methods known to the art, e.g. by Vilsmeier-Haack or Friedel-Crafts aroylations, as described in U.S. Pat. Nos. 4,089,969 and 4,347,186 (also to Syntex (U.S.A.) Inc.), both using dialkylamides; U.S. Pat. No. 4,353,829 (also to Syntex (U.S.A.) Inc.), using morpholides; and in U.S. Pat. No. 4,496,741 (to Merck); and the resulting ester saponified by conventional methods to yield a 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid.
U.S. Pat. No. 4,874,871 (also to Syntex (U.S.A.) Inc.) discloses a method of preparing 2,3-dihydro-1H-pyrrolizine-1-carboxylic acid and related compounds from pyrrole in the following manner: ##STR3##
where X and X' are independently halogen;
Y is --OH, --OM.sup.+, wherein M is an alkali metal; or --NRR' (where R is lower alkyl and R' is lower alkyl or aryl, or --NRR' is the residue of a saturated cyclic amine); and
Z is Li, MgCl, or MgBr. PA1 R.sup.2 is optionally substituted phenyl; PA1 R.sup.3 is Cl or --NR.sup.4 R.sup.5 (where R.sup.4 and R.sup.5 are independently C.sub.3 -8 alkyl, or --NR.sup.4 R.sup.5 is morpholino, piperidino, or pyrrolidino); and PA1 X is Cl or Br.
According to U.S. Pat. No. 4,874,871, the (.+-.)-2,3-dihydro-1H-pyrrolizine-1-carboxamides or salts may be hydrolyzed to the corresponding acid and then converted to the corresponding esters by conventional means; and the esters 5-aroylated and hydrolyzed to afford 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids by the methods described in U.S. Pat. Nos. 4,089,969; 4,347,186; and 4,353,829.
The disclosures of these patents, and other patents and articles referred to throughout this specification, are incorporated herein by reference.